Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF, not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. The recent data suggest that approximately 85 and 75% of patients supported with continuous flow VADs (CF-VADs) will survive at 12 and 24 months, respectively. These survival rates are approaching those of heart transplant patients. However, bleeding has become a significant problem for the CF-VAD therapy. Thus it is critical to understand the bleeding risk of CF-VAD support and their underlying mechanistic origins. Given the potential of the CF-VAD therapy for end-stage HF patients and the need to reduce significant device associated complications, we propose to conduct a series of clinical, biological and bioengineering experiments to seek a better understanding of shear-induced hemostatic dysfunction (SIHD) and bleeding in HF patients supported with CF-VADs and their link to blood flow dynamics of CF-VADs and pre-existing hemostatic disorder of HF patients. Further we seek to uncover the underlying molecular mechanisms of SIHD for better medical management and to create a database of SIHD for VAD design refinements. Three specific aims of the proposed project are: (1) To determine temporal changes of biomarkers of SIHD in HF patients prior to and during CF-VAD support and to link these changes to post-implant bleeding events; (2) To model shear stress indices (SSI) of CF-VADs and link them to measured biomarkers of SIHD and Bleeding in CF- VAD patients with consideration of pre-existing hemostatic disorder and patient-specific SIHD sensitivity to SSI prior to receiving a CF-VAD; and (3) To elucidate underlying molecular mechanisms of SIHD associated with CF-VADs and to establish a database of biomarkers of SIHD for VAD design improvement. Altogether, a combination of clinical hematology, biological as well as bioengineering approaches will be used to derive the basic knowledge behind bleeding complications and to investigate the influence of device-specific non- physiological fluid dynamic characteristics like shear stress and exposure time on SIHD. The successful completion of this project will create a new knowledge of bleeding associated with CF-VADs. The new knowledge can be used by clinicians to refine bleeding risk stratification in patients for the improved quality of life and by engineers to develop less traumatic, next generation biocompatible VADs.